tbuckley/cabot-search huggingface dataset:
Co-primary endpoint analysis of HCRN GU 16-257: Phase 2 trial of gemcitabine, cisplatin, plus nivolumab with selective bladder sparing in patients with muscle-invasive bladder cancer (MIBC).
Authors: Matt D. Galsky, Siamak Daneshmand, Sara C Lewis, Kevin G. Chan, Tanya B. Dorff, Jeremy Paul Cetnar, Ronac Mamtani, Christos Kyriakopoulos, Mahalya Gogerly-Moragoda, Sudeh Izadmehr, Menggang Yu, Qianqian Zhao, Tomi Jun, Reza Mehrazin, John P. Sfakianos, Sumanta Monty Pal
Journal: Journal of Clinical Oncology (2023)

447 Background: Transurethral resection of bladder tumor (TURBT) plus systemic therapy has been known for decades to achieve durable bladder-intact survival in a subset of patients with MIBC but efforts to advance this paradigm have been complicated by a lack of (a) prospective studies, (b) rigorous approaches to assess and define clinical complete response (cCR), and (c) integration of novel therapies. Methods: Eligible patients were cisplatin-eligible with cT2-T4aN0M0 urothelial bladder cancer. Patients received 4 cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging including urine cytology, MRI/CT of the bladder, cystoscopy and bladder biopsies. Patients achieving a cCR (normal cytology, imaging, and cT0/Ta) were eligible to proceed without cystectomy and receive nivolumab q2 weeks x 8 followed by surveillance. Patients not achieving cCR were recommended to undergo cystectomy. Coprimary endpoints included (1) cCR rate and (2) association between cCR and 2-year outcomes. The key secondary endpoint was the impact of pre-specified baseline genomic alterations on outcomes. Additional biomarkers to refine patient selection were also explored. Results: Between 8/2018-11/2020, 76 patients were enrolled at 7 sites (male 79%, median age 69; cT2 = 56%, cT3 = 32%, cT4 = 12%). Median follow-up is 27 months. 72/76 patients underwent clinical restaging and a cCR was achieved in 33/76 (43%; 95% CI: 32%, 55%). One cCR patient opted for immediate cystectomy (ypTaN0M0). Outcomes are summarized in the Table. Baseline ERCC2, ATM, FANCC, or RB1 alterations were not, but tumor mutational burden ≥ 10 mutations/mb was, significantly associated with the composite endpoint of ypT0 (immediate cystectomy) or 2-year bladder-intact metastasis-free survival (BIMFS). On landmark analysis, VI-RADS (Vesical Imaging–Reporting and Data System) score (3-5 versus 1-2) on restaging MRI (central blinded review) was associated with inferior BIMFS (HR 4.5; p = &lt;0.01) and MFS (HR 19.3; p &lt;0.01). Circulating tumor DNA data will be presented at the meeting. Conclusions: TURBT followed by gemcitabine, cisplatin, plus nivolumab achieves stringently defined cCR in a substantial subset of patients with MIBC. ≥2-year bladder-intact survival is achieved in the majority of patients with a cCR. Clinical trial information: NCT03558087 . [Table: see text]
De novo prostate cancer in renal transplant recipients: A single-center study.
Authors: Arthi Sridhar, Binoy Yohannan, Harmanpreet Kaur, Neha Maithel
Journal: Journal of Clinical Oncology (2023)

326 Background: Renal transplant recipients (RTRs) are at an increased risk of developing solid organ malignancies. Given improved allograft survival and life expectancy, the incidence of prostate cancer (PC) in RTRs appears to be increasing. Previous studies have reported the incidence of PC among RTRs to be between 0.3% and 3.24%. Limited data is available on the clinical characteristics, treatment, predictive markers, and outcomes of PC in RTRs. Methods: We performed a single-center retrospective study of male RTRs who developed PC. We collected the following data on RTRs who underwent transplantation between January 1, 1999, and December 31, 2019: baseline demographics, cause of end-stage renal disease (ESRD), duration of dialysis prior to RT, type of RT (cadaveric vs. living donor), immunosuppressive regimen, interval from RT to diagnosis of PC, stage of PC, type of treatment received, allograft survival, and overall survival (OS) were collected. Results: Among 1093 male RTRs, 15 (1.37%) developed PC. The median age at diagnosis of PC was 60 (range, 49-75) years. Subject races were African American (n=7), Hispanic (n=3), White (n=3), and other (n=2). The median duration from transplant to diagnosis of PC was 72 (range, 12-156) months. PC was diagnosed at stage I in 13 patients, stage II in 1 patient, and stage IV in 1 patient. The management of these patients consisted of local radiation (LR) alone in 6 patients, LR with leuprolide therapy in 6 patients, and radical prostatectomy alone in 1 patient. The patient with stage IV PC was treated with leuprolide and abiraterone acetate and remains progression free at follow-up of 41 months. The 5-year OS for this cohort of patients was 73.3%. Allograft function was preserved in 13 patients 12 months after diagnosis of PC. No PC-related mortality was noted. Conclusions: The incidence of PC in our analysis appears to be consistent with prior published studies. Most of our RTRs with PC had early-stage disease with excellent 5-year survival. The current standard-of-care treatment modalities for PC appear to be effective in the management of these patients. Allograft function was preserved in the majority of RTRs with PC in this study. Further research is required to evaluate the predictive factors for developing PC in RTR.
Neoadjuvant chemotherapy (NAC) versus adjuvant chemotherapy (AC) in patients with clinically node-positive upper tract urothelial cancer (UTUC) who underwent radical nephroureterectomy (RNU).
Authors: Karan Jatwani, Arya Mariam Roy, Kristopher Attwood, Anthony George, Muhammad Salman Faisal, Vasanthan Muthusamy Kumarasamy, Stuthi Perimbeti, Changchuan Jiang, Gurkamal S. Chatta, Dharmesh Gopalakrishnan
Journal: Journal of Clinical Oncology (2023)

486 Background: UTUC is less common and associated with poorer stage-for-stage prognosis compared to urothelial bladder cancer. AC is regarded as a standard-of-care in high-risk UTUC based on superior disease-free survival compared to observation in the POUT trial, though fewer than 10% of patients in this trial had lymph node involvement. 1 CheckMate 274 revealed lesser magnitude of benefit with adjuvant nivolumab in UTUC compared to bladder cancer on post hoc analysis. 2 The preferred sequence of perioperative systemic therapy in node positive UTUC remains unclear. Methods: We queried the National Cancer Database for adult patients with clinically node positive (cTanyN1-3M0) UTUC diagnosed between 2004 and 2018. Patients were divided into two groups based on the perioperative treatment strategy - NAC or AC. Patients who did not undergo RNU were excluded from analyses. Fisher’s exact and Mann Whiney U tests were used to compare frequency distributions. Cox Proportional Hazards regression was employed for multivariate analysis of factors associated with overall survival. Models were adjusted for age, sex, race, income, educational level, clinical T stage, insurance status, and the Charlson Comorbidity Index. Results: A total of 862 patients were identified - 362 (42%) underwent NAC while 500 (58%) received AC. No significant differences were noted between the groups regarding age, sex, or insurance status. Patients with cT1-2 UTUC more often received NAC (27.9% vs 11.8%, P &lt;0.001) while those with cT3-4 disease more frequently received AC (38.9% vs 57.4%, p&lt;0.001). Rates of NAC vs AC were not significantly different based on clinical N stage (P = 0.35). Overall survival in the NAC group was significantly longer than the AC group (median of 47.1 vs. 20.2 months, log-rank P &lt; 0.001). On multivariable analysis, only the sequence of perioperative chemotherapy was independently predictive of overall survival (Hazard Ratio of 1.38 for AC, with 95% CI 1.14-1.68, P = 0.001). Conclusions: In this large retrospective analysis of outcomes among patients with clinically node positive UTUC who underwent RNU, NAC was associated with significantly longer overall survival compared to AC. References: 1) Birtle A, Lancet 2020; 2) Bajorin DF, NEJM 2021.
Increased prostate volume on transrectal ultrasound and magnetic resonance imaging are potential risk factors for acute urinary retention following transperineal prostate biopsy.
Authors: Maxwell Sandberg, Wyatt Whitman, Janmejay Hingu, Parth Thakker, Anita Rong, Caleb Bercu, Jacob W. Greenberg, Ronald Davis, Ashok Hemal, Matvey Tsivian
Journal: Journal of Clinical Oncology (2023)

308 Background: Prostate biopsy is one of the most frequently performed procedures in urology. Recently, there has been a nationwide shift towards offering transperineal (TP) biopsies due to a reduced rate of infectious complications compared to the transrectal (TR) route. While infection may be reduced, TP biopsy is not without complication, most notably, acute urinary retention (AUR). Estimates vary as to the true rate of AUR following TP biopsy. Further, some studies have reported higher rates of AUR following TP biopsy than TR. Here we report the rate of AUR following TP biopsy at a single academic institute and relate it to risk factors for developing AUR. Methods: Retrospective case-control study. All biopsies performed with TR ultrasound (TRUS) guidance using TP technique under general anesthesia in dorsal lithotomy with a grid template. TRUS volumes were recorded during the procedure, and MRI volumes were calculated by a trained radiologist pre-biopsy. Charts of men undergoing TP biopsy from 2012 to present were reviewed. AUR was defined as patients who reported inability to urinate within 72 hours post-biopsy and underwent thorough evaluation including PVR and relevant H&amp;P and required catheter placement. Independent samples t-test was run to relate AUR to risk factors pre/post-biopsy. Results: A total of 767 TP biopsies were completed in the study window, but not all had TRUS/MRI data. Total rate of AUR was 5.48% (N=42/767). Risk factors for AUR were increased TRUS (p=0.009, [6.49, 42.30]) and MRI prostate volumes (p=0.027, [2.90, 43.13]). Age, number of cores taken, and number of previous biopsies were not associated with AUR. Conclusions: While data is scant, the rate of AUR at our institution is consistent with current estimates in the literature. There is a growing body of evidence that the rate of AUR post-TP biopsy is higher than TR, but more investigation is needed. There is also a gap in the literature on risk factors predicting AUR after TP biopsy, however our findings are relatively consistent with the few studies currently published. Urologists must recognize patients presenting for TP biopsy with large volume prostates and consider altering management to prevent AUR. [Table: see text]
Baseline characteristics associated with PSA progression-free survival in patients (pts) with high-risk biochemically relapsed prostate cancer: Results from the phase 3 PRESTO study (AFT-19).
Authors: Rahul Raj Aggarwal, Glenn Heller, David W. Hillman, Han Xiao, Joel Picus, Mary-Ellen Taplin, Tanya B. Dorff, Leonard Joseph Appleman, Douglas Jay Weckstein, Akash Patnaik, Alan Haruo Bryce, Daniel H. Shevrin, James Mohler, Daniel M. Anderson, Arpit Rao, Scott T. Tagawa, Alan Tan, Scott E. Eggener, Charles J. Ryan, Michael J. Morris
Journal: Journal of Clinical Oncology (2023)

208 Background: In the Phase 3 PRESTO study, intensified androgen deprivation therapy (ADT) with apalutamide (APA) with or without abiraterone acetate plus prednisone (AAP), administered for a finite treatment period of 52 weeks, prolonged prostate-specific antigen progression-free survival (PSA PFS) in pts with high-risk biochemically relapsed prostate cancer (BRPC). We evaluated baseline factors associated with PSA PFS in this study. Methods: PRESTO is a randomized phase 3, open-label trial in pts with BRPC following radical prostatectomy (RP) and PSA doubling time (PSADT) ≤ 9 months (mo), without distant metastases on conventional imaging (NCT03009981). Pts were randomized 1:1:1 to receive a finite 52-week treatment course with ADT, ADT + APA, or ADT + APA + AAP, stratified by PSADT (&lt; 3 vs 3–9 mo), with post-treatment follow-up. Baseline factors associated with PSA PFS including Gleason sum at RP (6-7, 8, ≥ 9) were analyzed in a post hoc fashion. Results: 504 pts were randomized to ADT alone (N = 167), ADT + APA (N = 168) or ADT + APA + AAP (N = 169). Baseline patient characteristics including Gleason sum at diagnosis, serum PSA and PSADT at study entry, time interval from radical prostatectomy, and receipt of prior radiation (none, adjuvant, salvage) were well balanced across the three treatment arms. At the first planned interim analysis, both experimental arms significantly prolonged PSA PFS compared to the control arm (median 24.9 mo for ADT + APA vs 20.3 mo for ADT, HR = 0.52 (95% CI: 0.35–0.77); median 26.0 mo for ADT + APA + AAP vs 20.0 mo for ADT, HR = 0.48 (95% CI: 0.32–0.71)). Across the study cohort, Gleason sum ≥ 9 at diagnosis was associated with shorter PSA PFS (median 21.9 mo for Gleason ≥ 9 vs. 31.1 mo for Gleason 8 vs. 25.2 mo for Gleason 6-7, log-rank p-value = 0.0409). In addition, within each treatment arm, a shorter observed median PSA PFS was detected for patients with Gleason ≥ 9 prostate cancer. Serum PSA and PSADT at study entry, time from prior radical prostatectomy, and prior radiation were not associated with PSA PFS in the overall study cohort or in individual study arms. Conclusions: Gleason sum ≥ 9 prostate cancer at diagnosis was associated with shorter time to PSA progression following subsequent intensified ADT administered for a finite treatment interval in BRPC. Follow-up is ongoing to integrate genomic profiling of primary prostate cancer tissue with these results and validate with longer term endpoints including metastasis-free survival. Clinical trial information: NCT03009981 .
Effect of Janus kinase (JAK) signaling inhibition on lineage plasticity and drug sensitivity in castrate resistant prostate cancer.
Authors: Samir Zaidi, Joseph Minhow Chan, Jillian Love, Jimmy Zhao, Manu Setty, Kayla Lawrence, Anuradha Gopalan, David Goodrich, Michael J. Morris, Yu Chen, Wouter Karthaus, Dana Pe'er, Charles L. Sawyers
Journal: Journal of Clinical Oncology (2023)

227 Background: Despite the remarkable successes of targeted cancer therapies, certain cancers, including lung, breast, and prostate cancer and melanoma, invariably become resistant to therapy. One mechanism of secondary resistance—lineage plasticity—arises when cells alter their identity and transition into aggressive states. In the case of prostate cancer, cells can acquire a neuroendocrine histology. This is often associated with a loss of tumor suppressor genes, such as TP53, RB1, and PTEN. However, while these genomic events initiate plasticity, tumor progression is not always associated with successive genomic alterations. This, in essence, not only poses a clinical challenge, but also confronts us with a wide-open biological question—what are the molecular underpinnings of lineage plasticity, and importantly, can the process be reversed? Methods: To study the temporal evolution of lineage plasticity and its relationship to androgen receptor signaling inhibitor (ARSI) resistance, we utilized genetically engineered mouse models (GEMMs) and murine organoids that were deleted for Tp53, Rb1, and/or Pten. Single cell RNA analyses were utilized to dissect which genes and pathways were up-regulated and most associated with the progression of plasticity. Plasticity-associated genes and pathways were perturbed using FDA-approved inhibitors or genetic editing tools. The presence of these pathways was confirmed in a subset of metastatic index lesions obtained by radiologically guided biopsies and as visualized by metabolic imaging. Furthermore, relevant findings were functionally validated in human tumor derived organoids (“tumoroids”). Results: Using GEMMs and organoid models, we found the lineage plasticity depended on increased Janus Kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Pharmacologic inhibition using FDA–approved inhibitors of JAK/STAT (ruxolitinib) and FGFR (erdafinitib), or through genetic knockdown, demonstrated increased androgen receptor (AR) signaling and restored ARSI sensitivity. These findings were further validated in a subset of ARSI-insensitive human tumoroids. By performing single cell RNA sequencing on mCRPC tumors biopsies, the presence of highly plastic JAK/STAT- and FGFR-high cells were confirmed, with implications for stratifying patients for clinical trials. Conclusions: JAK/STAT and FGFR signaling pathways promote lineage plasticity and result in complete insensitivity to androgen receptor signaling inhibitors (ARSIs). FDA-approved inhibitors of JAK/STAT (ruxolitinib) and FGFR (erdafitinib) synergize to reverse lineage plasticity and restore ARSI sensitivity.
Association of serum lactate dehydrogenase (LDH) isozyme with prognosis of patients with metastatic clear cell renal cell carcinoma (mCRCC).
Authors: Hayato Takeda, Go Kimura, Jun Akatsuka, Yuki Endo, Masato Yanagi, Hikaru Mikami, Hiroya Hasegawa, Akifumi Katsu, Ryota Funato, Mami Taniuchi, Yuka Toyama, Yukihiro Kondo
Journal: Journal of Clinical Oncology (2023)

709 Background: LDH isozyme is a tetramer of two subunits, H chain and M chain, and is present in all living tissue. Five types of molecular forms characterize the LDH pattern, and tumor tissues relatively consist LDH-4 and LDH-5, composed with a high ratio of the M chain, compared to normal tissues. This study analyzed the association between LDH isozyme and prognosis of mCRCC after nephrectomy. Methods: Clinical records of mCRCC patients those who were initially diagnosed M0 disease at Nippon Medical School between 2012 and 2016 were retrospectively reviewed. LDH isozyme values before operation and at time of metastasis were checked. Isozyme patterns were classified into 6 types, LDH 1-5 dominant and common type, according to the most composed molecular form. Results: Out of 38 patients, 33 patients (87%) were male, 5 patients (13%) were female. Median age was 65 years old (36-87). pT1 was seen in 3 cases, pT2 in 4, pT3 in 27, and pT4 in 4. Pathological grade 2 were 9 cases, G3 in 21, and G4 in 8. As for the IMDC risk, favourable was 2 cases (5%), intermediate in 26 (68%) and poor in 10 (26%). Median LDH was 163 IU/L (113-317), and isozyme dominant pattern were as follows: LDH-2 in 9 cases (24%), LDH-3 in 6 (16%), LDH-4 in 4, LDH-5 in 11. 8 cases were common type, and no cases showed LDH-1 dominant. Median time from surgery to recurrence was 10 months (1-104), median follow-up period after recurrence was 18 months (4-72). 16 deaths occurred. No significant correlation was seen between pre-operative LDH isozyme pattern and pathological grade or pT stage. Pre-operative LDH isozyme did not correlate with the time to recurrence (p=0.7420). The median OS for LDH-4 dominant at the time of metastasis was 10.9 months, significantly shorter than other isozyme types (P=0.0134). Conclusions: LDH-4 dominant isozyme pattern at the time of recurrence has a short OS, proposing as a prognostic predictor in mRCC.
A phase 1b/2 study of batiraxcept (AVB-S6-500) in combination with cabozantinib in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC).
Authors: Neil J. Shah, Matthew T Campbell, Shifeng S. Mao, Moshe Chaim Ornstein, Naomi B. Haas, Xin Gao, Hans J. Hammers, Holavanahalli Keshava-Prasad, Hongxia Yan, Vanessa Esquibel, Robert B. Geller, Katy Beckermann
Journal: Journal of Clinical Oncology (2023)

666 Background: Activation of the GAS6/AXL pathway promotes tumor cell proliferation; high levels of GAS6 and AXL have been associated with drug resistance and decreased survival. Batiraxcept is an ultra-high affinity decoy protein that captures GAS6, preventing it from activating AXL signaling. Serum soluble AXL (sAXL)/GAS6 ratio correlates with response to batiraxcept in advanced ovarian cancer. Batiraxcept in combination with cabozantinib is being evaluated in patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC) in this study. Prior studies of cabozantinib in similar pt populations have shown an overall response rate (ORR) ranging from 15 – 32.5% and progression-free survival (PFS) from 3.7-7.2 months (mo). Methods: Key eligibility criteria include previously treated ccRCC pts, excluding prior cabozantinib. Objectives were to determine the safety of batiraxcept plus cabozantinib 60 mg, the recommended phase 2 dose (RP2D), ORR, PFS, duration of response. Correlative endpoints included assessment of baseline serum sAXL/GAS6 with ORR and PFS. Results: In Phase 1b (P1b), 26 pts received at least one dose of batiraxcept with cabozantinib (16 pts - 15 mg/kg; 10 pts - 20 mg/kg). Median age was 60 (range 40-81), male 85% (n=22), IMDC intermediate/poor risk 77% (n=20). All pts received prior immuno-oncology (IO) therapy, 54% (n=14) also received VEGF-TKI; 85% (n=22) received 1 to 2 prior lines of therapy (range 1-6). Median follow-up time was 11.6 mo (range 3.7-18). The RP2D is 15 mg/kg. Related adverse events (AE) any grade and grade ≥ 3 were 100% and 39% (n=10), respectively. Cabozantinib dose reductions occurred in 54% (n=14). AEs of special interest were grade 1 or 2 infusion related reactions, 27% (n=7). Batiraxcept was discontinued due to disease progression 62% (n=16) or toxicity 12% (n=3). The table shows P1b efficacy, ORR of 42%, median PFS of 9.3 mo, and DCR of 84%. Twenty (77%) pts had high baseline sAXL/GAS6 levels; ORR was 55% (11/20) with mPFS of 9.3 mo, compared to 0% ORR and mPFS 6.4 mo in the low sAXL/GAS6 pts. Conclusions: Batiraxcept was well tolerated when combined with cabozantinib. No new safety signals were noted. Efficacy for the combination is encouraging compared to historical cabozantinib monotherapy data. Higher GAS6 levels were predictive for treatment response. The P2 accrual is complete and efficacy data are maturing. A P3 trial plans to evaluate the efficacy in ccRCC patients who have progressed on IO-based and VEGF-TKI therapies. Clinical trial information: NCT04300140 . [Table: see text]